To help determine the mechanisms whereby amiodarone (a benzofurane compound) improves cardiac symptoms in patients with hypertrophic cardiomyopathy refractory to standard medical therapy, radionuclide cineangiography at rest and during matched levels of exercise was used to assess left ventricular functional changes. Ten patients were treated with high dose oral amiodartone (800-1600 mg per day for 10 days) and compared to no medications and calcium channel blocker therapy (either verapamil or nifedipine). All patients had refractory symptoms with calcium channel blockers but 8 of 10 were clinical responders to amiodarone (clinical response defined as 100% increased exercise capacity and/or greater than 50% decrease semi-quantitative symptom score). These 8 clinical responders were also compared to another group of patients with hypertorphic cardiomyopathy and similar clinical improvement during treatment with the calcium channel blocker, verapamil. No patient manifested significant changes in left ventricular systolic function (rest ejection fraction, exercise ejection fraction, or ejection rate indices); however, both an increased peak filling rate and a decreasd time to peak filling rate (suggesting improved diastolic filling), were seen in 66% of clinical responders during verapamil therapy, but in only 1 of 8 clinical responders with amiodarone therapy. Thus, in patients with hypertrophic cardiomyopathy, diastolic filling changes contribute to clinical improvement during verapamil treatment, but cannot explain the mechanism underlying symptom benefit during amiodarone therapy.